ABSTRACT The incidence of myopia (near-sightedness) has increased in alarming rates over the last 30 years, creating the risk for retinal detachment and costing billions in healthcare dollars for refractive corrections. The rapid increase in myopia suggests that environmental factors may play a key role. We propose that the reason for the accelerating incidence of myopia is the mesopic lifestyle shared by people in modern society. The mechanism driving refractive development has been localized to the retina, but the retinal pathways and biochemical signaling remain unknown. We hypothesize that mesopic illumination levels (indoor lighting) induce myopia by stimulating specific retinal pathways which alter dopamine and melanopsin signaling. This hypothesis is supported by pilot data that shows that scotopic (night sky) and photopic (sunlight) illumination levels reduce lens-induced myopia, while mesopic illumination increases lens-induced myopic shifts. Additionally, a growing number of animal and human studies show protective effects of bright light on myopia development. This hypothesis supports three innovative ideas that will be tested: 1) ambient lighting may establish a tonic, steady state in retinal signaling upon which visual input is processed, such that scotopic and photoic illumination levels slow myopic eye growth and mesopic illumination promotes myopic eye growth, 2) dopamine signaling underlies these effects such that mesopic illumination produces the lowest level of dopamine bioavailability when combined with disrupted visual input, and 3) melanopsin-containing intrinsically photosensitive retinal ganglion cells (ipRGCs) may signal eye growth under photopic illumination. Aim 1 will examine whether different ambient illumination levels alter susceptibility to myopia by measuring refractive error and ocular biometry of mice housed under different lighting conditions with and without lens defocus. Aim 2 will investigate the role of dopamine modulation under each ambient illumination using genetic and pharmacological approaches to examining dopamine receptors and dopamine metabolism. Aim 3 will determine whether melanopsin mediates refractive development in each ambient illumination by using melanopsin-deficient mouse models. The results will provide new insights about how rods, cones and ipRGCs regulate visually-driven eye growth through dopamine and melanopsin signaling. These experiments will identify clinically relevant environmental factors that may alter susceptibility to myopia while also providing potential therapeutic drug targets to slow or stop myopia progression.